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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Reddy, Duttala Obula, M.D. 7/13/01

  

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 

Rockville MD 20857

 

WARNING LETTER

JUL 13 2001

CERTIFIED MAIL - RESTRICTED DELIVERY
RETURN RECEIPT REQUESTED

Ref: 01-HFD-45-0401

Duttala Obula Reddy, M.D.
Psychiatric Associates
1124 South Sixth Street
Springfield, Illinois 02703

Dear Dr. Reddy:

Between September 20 and December 19, 2000, Ms. Susan D. Yuscius, representing the Food and Drug Administration (FDA), met with you and your staff to investigate allegations of regulatory non-compliance in your conduct of the following clinical studies performed for Eli Lilly and Company:

Protocol (b)(4) of the investigational drug R-fluoxetine hydrochloride; and

Protocol (b)(4) of the investigational drug Zyprexa (olanzapine).

This inspection is a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to validate clinical studies on which drug approval may be based and to assure that the rights and welfare of the human subjects of those studies have been protected.

From our evaluation of the inspection report and the documents submitted with that report, we conclude that you did not adhere to all pertinent federal regulations and/or good clinical investigational practices. We note that at the conclusion of the inspection, Ms. Yuscius presented and discussed with you the items listed on Form FDA 483, Inspectional Observations, in which you provided explanations regarding the failure to report an adverse event for subject 3020, and informed consent documentation issues for subjects 3001,3007,3013 and 3024, enrolled in protocol (b)(4); and the failure to obtain a visit 1 urinalysis from subject 1653 enrolled in protocol (b)(4). Although we accept your explanations for the violations noted above, we wish to remind you that you failed to meet your regulatory obligations as the investigator of record in the conduct of your studies and consider this practice unacceptable for the following:

SUMMARY OF VIOLATIONS RELATED TO YOUR FAILURE TO CONDUCT THE INVESTIGATION ACCORDING TO THE SIGNED INVESTIGATOR STATEMENT [21 CFR 312.60 and 21 CFR 312.S3(c)(1)(vi)(d)]

Protocol (b)(4)

You failed to personally conduct or adequately supervise the conduct of protocol (b)(4), or have a qualified sub-investigator perform, a large number of physical examinations. During the inspection, you admitted that either a study coordinator or your sub-investigator, (b)(4), Ph.D., performed the majority of the screening and early termination physical examinations and that you subsequently signed the source documents to indicate your review. We do not accept your response that (b)(4), Ph.D., was capable of conducting physical examinations based on Dr. (b)(4) experience as an ECG technician and an anatomy professor. Your failure to personally conduct or supervise the study led to non-physicians performing Clinical Global Impression (CGI) assessments and physicals at screening and early termination visits for a majority of subjects enrolled in this study.

SUMMARY OF PROTOCOL VIOLATIONS (21 CFR 312.60)

Protocol (b)(4)

1. You failed to personally conduct, or have a physician sub-investigator conduct, a large number of CGI ratings. We note that the protocol specifically requires that a physician perform the CGI assessments.

For eleven subjects (subject 3001, visit 6; subject 3004, visit 5; subject 3005, visit 6; subject 3006, visits 6 and 7; subject 3007, visits 2 and 3; subject 3008, visits 6 and 7; subject 3011, visits 1,3, and 5; subject 3012, visit 3; subject 3013, visits 2 and 4; subject 3014, visits 2 and 3; and subject 3015, visit 2), study records initially identified either a study coordinator or non-physician sub-investigator as the CGI rater; however, these records were subsequently changed to indicate that you were the CGI rater. During the inspection, you acknowledged that you probably did not see these subjects and that you may have made these ratings based on secondhand information received from a study coordinator or non-physician sub-investigator.

2. You failed to perform the CGI evaluations at the early-termination visits for 15 subjects, and the CGI evaluation at visit 10 for subject 3004.

3. You enrolled subject 3001, despite a past diagnosis of bipolar disorder and failure to have the required washout period for Prozac, and enrolled subjects 3003 and 3006 despite not having protocol-required washout period for Celexa and/or Zyprexa.

Protocol (b)(4)

1. You enrolled subject 1655, despite a past diagnosis of schizophrenia and treatment with clozapine within four weeks prior to visit 2.

2. You failed to obtain a screening hepatitis panel for subject 1656. In addition, this subject received a prohibited concomitant medication, Ambien, on seven occasions during hospitalization while enrolled in the study. We note your agreement with these observations.

SUMMARY OF VIOLATIONS RELATED TO RECORDKEEPING AND CASE HISTORIES [21 CFR 312.62(b)]

Protocol (b)(4)

1. Study records for subjects 3005 and 3008 contain electrocardiogram (ECG) tracings that were taken at exactly the same time (December 29, 2000, at 15: 19) and appear to be misrepresented. We note that a) only one of these subjects, subject 3005, had a visit scheduled for December 29, 2000; b) at least one of the tracings in question contains the initials of subject 3008 in association with the ID number of subject 3005; and c) there was no original ECG tracing among study records for subject 3008. During the inspection, you agreed that the ECG strips for these subjects appeared to be from the same person. In addition, your study coordinator and the president of the site management organization where the study was conducted both acknowledged that there was only one examining room and that only one ECG could be produced at any given time.

2. Study records for subjects 3007, 3012, 3022, and 3025 contain CGI evaluations reportedly performed by you on 3/27/00, when a study coordinator's calendar indicates that you were not available on that same date to see study subjects. When asked during the inspection, you stated that you based these ratings on secondhand information, obtained via telephone, from a study coordinator or non-physician sub-investigator despite the protocol requirement that a physician conduct these evaluations.

3. There were no source documents available to support case report form (CRF) entries indicating that early termination physical examinations were conducted for subjects 3008, 3022, and 3023.

In view of the nature of violations discussed above, we request that you inform this office, in writing, within 15 working days of your receipt of this letter, of the actions you have taken or plan to take to prevent similar violations in the future. Failure to adequately and promptly explain the violations noted above may result in further regulatory action.

If you have any questions, please contact Dr. Antoine El-Hage, at (301) 594-1032, FAX (301)827-5290. Your written response and any pertinent documentation should be addressed to:

Antoine El-Hage, Ph.D.
Branch Chief
Good Clinical Practice II, HFD-47
Division of Scientific Investigations
Office of Medical Policy
Center for Drug Evaluation and Research
7520 Standish Place
Rockville, MD 20855

Sincerely yours,

/s/

Martin H. Cohen, M.D.
Acting Director
Division of Scientific Investigations, HFD-45
Office of Medical Policy
Center for Drug Evaluation and Research
7520 Standish Place
Rockville, MD 20855